Sunday, April 27, 2008

Calorie restriction, TOR signaling, and aging

Now that I've given some pointers to information about how TOR signaling is involved with metabolism (see here), it seems like an opportune time to mention a recent research announcement in this general area.

How Dietary Restriction Slows Down Aging (4/17/08)
University of Washington scientists have uncovered details about the mechanisms through which dietary restriction slows the aging process. Working in yeast cells, the researchers have linked ribosomes, the protein-making factories in living cells, and Gcn4, a specialized protein that aids in the expression of genetic information, to the pathways related to dietary response and aging.

Here's the key background:
Previous research has shown that the lifespan-extending properties of dietary restriction are mediated in part by reduced signaling through TOR, an enzyme involved in many vital operations in a cell. When an organism has less TOR signaling in response to dietary restriction, one side effect is that the organism also decreases the rate at which it makes new proteins, a process called translation.

The researchers investigated various strains of yeast cells that had low rates of protein production, but increased lifespan. They found that a common characteristic of such cells was mutations to one part of the cell's ribosomes, the complex of RNA and certain proteins which manufactures all new proteins in the cell. The result of these ribosome changes was a decrease in the production of most proteins, except for one, called Gcn4, a transcription factor, whose production increased. The effect seems to depend on the same pathway affected by reduced TOR signaling. Gcn4 is associated with control of amino acid synthesis, and is activated when a cell is starved for amino acids.
To make the link between Gcn4 and longevity, the scientists then asked whether preventing the increase of Gcn4 would block life span extension. In every case, cells lacking Gcn4 did not respond as strongly as Gcn4-positive cells.

"The increased production of Gcn4 in long-lived yeast strains, combined with the requirement of Gcn4 for full life-span extension, makes a compelling case for Gcn4 as an important downstream factor in this longevity pathway," Kaeberlein said.

One might speculate that increased Gcn4 production somehow helps the cell cope with lack of nutrients, and one effect is that the cell takes steps to conserve its resources and slow the rate of aging.

Since reduction of TOR signaling is one way to bring about this effect, TOR inhibitors might help slow aging and increase lifespan, at least in yeast. However, since TOR affects so many other cell functions, the chance for harmful side effects of reduced TOR signaling is high.
"The role of TOR and translation in aging is known to be conserved across many different species, so it's plausible that this function of Gcn4 is conserved as well," Kennedy said. Future research will be aimed at testing this hypothesis.

"Clearly TOR signaling is one component, and perhaps the major component, of the beneficial health effects associated with dietary restriction," said Kaeberlein. "The difficulty with TOR as a therapeutic target, however, is the potential for negative side effects. As we learn more of the mechanistic details behind how TOR regulates aging, we will hopefully be able to identify even better targets for treating age-associated diseases in people."

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